Production of thiazolylamines



Patented May 19, 1953 wenn Si wh'ef'em it is: sieetei geen@ e lv'dnvanimi aralkyl and aryl groups, and the tvvl i'sls valencesindicate'substituents on the nitrogen atom, have previously been"prepared by the condensation of a vselected B-halothi'aiole with thecorresponding; secondary aniine (having y:av-'hydrogen atom in plce ofthe 2- thiaz'ole nucleus sliown in the formula aboveleji'f. Suchcondensatins pbiieatien Deeember 15, 194s,

(Cl. M50-306.3)

2 i v videhsuofh a Aprocess WuhiclrproceedsK frein a specific type ofsecondary amine to a cyanamid, then to a thiourea, and -`finally to thethiazolylamine. Still a furtlir object of this invention is theprovision of certain novel compounds useful in preparing certainthiazolylamines according to l d. G- alsaciens@ G l ei; flf vtvlivl,tfii allyl', allxy, Halo, and Hydroxy ri'iiclearly,-Su.i stitutedderivatives thereofhwherein G and G are alkyl or aralkyl radicals; whichmay be tle same or dfferenbl or the remainder of a heterocyclic ring,and whereinpislan integer from l to 4, inclusive, may be converted to anitrile of the formula:

wherein nz--Gfand @if have; the values7 given above, by-riieacizienoffthe-nitrileggoup (-1 N) thereof; vyitlril hydrogen' sulfide,rnv(I-I'zS). Th s is Stelgflifiourfprpoess:

Wehevefureherfound da/altri@ of the thiourea (4) may be reacted with a.reagent 5), which is a compound having the formula wherein R is aradical selected from the group consisting of hydrogen, alkyl, aralkyland aryl, said Rs may be the same or different, and wherein X is ahalogen selected from the group consisting of chlorine, bromine andiodine, or an agent which is convertible to such a haloaldehyde orhaloketone. The thiourea is thus transformed into a 2-thiazolylamineofthe formula:

H2 G l .i-NCH2f.-N\

wherein n, Y, G, and G have the values previously assigned and wherein Ais a 2-thiazole ring oi the formula:

wherein R has the hereinbefore assigned values, depending upon thereagent employed in reaction with the thiourea. This is Step III in ournew process.

It should be obvious from the foregoing, that, by our new process, wehave provided a new and simple process for converting a specific type ofsecondary amine to a specic type of tertiary 2- thiazolyamine, or, ifdesired, t0 any intermediate phenyl, m-meth'oxyphenyl, p-chlorophenyl,o-

hydroxyphenyl, p-hydroxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl,o-iodophenyl, cyclopentyl, cyclohexyl, chlorocyclopentyl, hydroxycyclo-`hexyl, methoxycyclohexyl, ethylcyclopentyl, 5.-

bromo-Z-thienyl, 2-thieny1, 5-methyl-2-thienyl,

et cetera, wherein n is an integer from one to four, inclusive, andwherein G and G' are alkyl ,or aralkyl radicals which may be the same,different or the remainder of a heterocyclic ring, for example, methyl,ethyl, propyl, isopropyl, butyl, amyl, isoamyl, octyl, decyl,tridecyLbenzyl, phenethyl, pyrrolidino, piperidino, morpholino,thiomorpholino, methylpiperidino, et cetera.

Representative secondary amines which may be employed areN2-propyl-N2-isobutyl-N3-(pdimethyl N2 (S-thenyl) 1,2 propanediamine,

N,N dimethyl N [2-(5-methylthenyDlethylenediamine, N,N dipropyl N [2-(3-chlorothenyD] ethylenediamine, N,N dimethyl N' (2-thenyl)methylenediamine, N1,N1-

4 dimethyl- NS (2-thenyl) 1,3 propanediamine, N,N dimethyl Nbenzylethylenediamine, N,N- dimethyl N benzylmethylenediamine, N,N-diethyl N benzylmethylenediamine, N,N diethyl N benzylethylenediamine,N,N dibutyl N benzylethylenediamine, N,N dibutyl- Nbenzylmethylenediamine, N,N dicyclohexyl- N benzylmethylenediamine,N,N-dihexyl N'- benzylemethylenediamine, N ethyl N cyclohexylmethyl Nbenzylethylenediamine, N- ethyl N methyl.- N benzylmethylenediamine, Nmethyl N ethyl N benzylethylenediamine, N,N- dimethyl N'(p-chlorobenzyl) ethylenediamine, kN,N-dimethyl N' (p-ethylbenzyl)ethylenedlamine, N-methyl N propyl N (p-ethylbenzyl) ethylenediamine, N,N dimethyl N (p-methoxybenzyl) methylenediamine, N,N dimethyl N'(p-methoxybenzyl) ethylenediamine, N,N-diethyl N (methoxybenzyl) Aethylenediamine, N1,N1-dimethyl N2 benzyl 1,2- propanediamine, N AmethylN propyl N' (m-fethylbenzyl) ethylenediamine, N'- methyl N -chexyl lNjbenzylethylenediamine, l2 piperidino N (o-methylbenzyl) ethylamine,piperidino N benzylmethylamine, 2 morpholino N benzylethylamine, N,Ndiethyl N (Ll-methoxybenzyl) methylenediamine, N1,N1 diisopropyl N"d(pmethylbenzyl) 1,3 propanediamine, N1,N1 dipropyl N2 (p-hydroxybenzyl)1,2 propanediaminve, N1,N1y dihexyl N3 (2,4-dichlorobenzyl 1,3`butanediamine,l Nl methyl N1- hexyl N4' -,(2|-thenyl) 1,4butanediamine, morpholinov N cyclopentylmethylamne, l- 2, orS-piperidinc N (Z-,thenyb propylamine, et cetera. l 1

Step I.-The rst step in the process consists in reacting a cyanogenvhalide (3) with a secondary amine (l) given'above to obtain asubstituted cyanamide, as is shown by the following equation: I

wherein Y, n, G and G have the values previously given, and vwherein Xrepresents4 a halogen selected from thegroup consisting vof chlorine,bromine and iodine. vEmployment of cyanogen chloride or cyanogen bromideis Iordinarily preferred, since their employment'ordinarilyv results ina better yield of the cyanamide.

The reaction fmay be carried out in any convenient manner, such' as byadding the cyanogen halide to thesecondary amine. If desired, water `orany suitable organic solvent, e. g., ether, methancl, carbonltetrachloride, benzene, et cetera, may be used as avmedium for thereaction. The usual temperature range for the reaction is between about-30 degrees and about 50 degrees centigrade, the range between -10degrees and 10 degrees centigrade being preferred. The preerredprocedure is to add the cyanogen halide slowly, say, ,over a period offteen minutes, to the secondary amine, which has been dissolved in asuitable solvent and cooled by a conventional arrangement. vStirring oragitation is preferably employed during the reaction period to ensureefcient contact of the reactants. A portion of a basic material, e. g.,sodium hydroxide or potassium hydroxide, may be'addedfto the mixture,after lthe reaction is complete, to liberate the cyananride from itshydrohalide, if desired. The

essere 'cvanamide may then be in any con'- venient frnanner, such es 'bythe use 'of ether, and dried. suitable 'methods "or extraen@ `eine'purilation 'Will 'be apparent to vone 'skilled .iin the fait.

Step H.#Ti-1i's step of `the `process consists in reaetingithesubstitutedcyanemide of Step'I with hydrogen slde 11:0 -convert 'thenfitrile 'gr-eue L -CEN? of the -Slesttube evene-mide to VIl" 'thiourealgroup as illustrated by me renewing equation:

ployed are ammonium hydroxide, triethylamine trietharrolamine,4pyridine, et ieetera., lernmenium hydroxide -being preferred. 'Thetemperature range for this .step is fbetweensebout '20 .degrees andabout. `10i) y,degrees centigraide with the preferred range beingbetween :about -f10 degrees :duidl 10 .degrees oentigrade. 1f a suitablesolvent has been used, vafter .asmoient period of time. crystelsusueliyform, which may then flee filtered oi. The .mother .liquor canfthenvordinairily .be

.concentrated .and Vanother batch 'of '.orystals `.ole-

tained. The Cryst-els v.thus obtained may be pil-ried in ltiny.c'cnwenient gmannergsuchfas .byrecryse y,tei'llizetion, which Wlillfbeepperent'to .'onef'ski'lled iii-the ent. y

Step 1II.-This.step involves reacting ftheisub'- stituted thiouree.vproduced .in Step {II with a. compound having thegeneral formulawherein Ris selected Alfrornthe ygroupcrinsistirig hydrogen, eikyi,ceireviikvl and eryirradicais, v"the seid "Rfs may rbe lthe saine Yorvdifferent, *and wherein X is a. haicgen lselected from l"the groupconsisting .of ohlor-ine, bromine .andviodine f lhis step ,of our ,novelreaction iseries is :illustrated by the 4following equation:

or emmer. Representative -eempeunas einem the formula wherein R andX'h'ave velues hereinbefore given are, for example monochioroacetone,achioroiro'pi'or-mid'ehxnieA iodoaicetaidehyde,wieromophenviiaeetadehyde, @Qaschioroberizviaphenyl ketone,:Qa-.bromobenzylibenzyi ketoneitaecmoro- Aphenetisigll)oenzvii ketone,civ-ehlomdi'butyl ketone.. acetafis and hemieacetels yof iheiafehaloelde'hydes., et cetera.

The` .temperature renee to be .maintained in ,this step Iis hetwe'en.about ,room 'temperature .and about 1120 degrees en-tiered@ with -.theoptimum :range being between .about 70 and .89 degrees centigrade.However., if metals lare employed. which represents .aMeferred-emhediment of the present invention, .atempereture rof .etleast 5.0 degrees centisrede may he employedrto ensure the immediate.hydrolysis .of the aetal. lf .temiperatures remove remix are used, ,itf-s desirable that pressure-.be employed. .'Ihe .reaction .may .beconducted in .any convenient such es Joy dissolving the reactants fa`suitable readtion medimn frand bringing'the temperature to athedesiredlevel; ,stirring .or agitation is .preferably employed to Y.ensureefcient ioonta'et of the ree estante. The greed/'ion time is notvcriticaleuml will vary .considerably deiner-mine upon .sev-.eralfactors. .A petition ofhesemaerialr---S0sium hydroxide, .may he .addedfet the 'termination .of the reaction to liberate 'the 'amine from itsacid saitfi-'f formed.

Haioacetejl, such as chioroaoetal the d-iethyl acetai ofehloroacetaldehyde, erre p'referred reagents since lthey are .readily`obtainable and .ecenomieei The ruse of e .haioacetal yis y.passibley.ieeczmise fof en equilibrium which `.shifts iaiverabiy lto Yfprod-uce'a haloaeetaldehyde in the lpresence @i lrre-ter and/forvaed.;saidhailoaoetaldehyde .may .he generated in situ, if desired. Thefollowing equation `.errerrrpiiiies,the reactien which makes possiblethefempioyment auf :,af-m1oaeeta1:

eee like l wherein .X ,is .e halogen @elected from 'the y,group.consisting of .ehlerine, .-bromine and iodine. and wherein-miseriiintegerffremil to Gaine/lesive. ais 'to :be emphasized, heweven :that.although en .ariete-1 employed. -the swbetence iareeiex down :into :en-felidehyde having the formula wherein 'the TR .has @the velueshereinbeiore .essigned.

The product of the reaction of ythis step is e. thiezolvi .ring :havinga .nitregen l.fsiilsxstitnem; .in -vthe -mpositioe end, .dependent-upon,the v.reesent used, various substituents mitheveand fepositions. Forexample, if an a-h'aloaldehyde other than 4ecetendehivde -is -meactedyin ithe `method of yfthe third lstep, .a fesdbstituted :ithiazol-ylcom- -ipound iresuits. Tf ,aha'lomethylfk'etoneis reaioted in ithemethod .of fithe third istep, fle .e1-substituted thiazolyfl `'comprimid.-results, rand, am af-haile- 'itiereinbefore given, zthe saidRismatyibe ithe 'same '75 @ketone ether than ,-eilsielomethyl -lc'ctone1reacted, a 4- and -substituted thiazolyl compound is the product.

The products of the present invention are therapeutic agents useful inthe eld of antihistaminics.

The following examples are given to illustrate the practice of thepresent invention but are not to be construed as limiting.

Eampze L Pmmmribn of N-(z-dimethyzaminoethyl) -N- (benzyl) -cyanamideCyanogen bromide was prepared by gradually adding a solution of 6.8grams (0.1 mole) of potassium cyanide in 25 milliliters of water to amixture of 16 grams (0.1 mole) of bromine and 25 grams of ice. Afterstanding for about ten minutes at zero to five degrees centigrade, theresulting cyanogen bromide solution was added with constant stirring toa mixture of 17.8 grams (0.1 mole) of N,N-dimethyl-N-benzyl-ethylenediamine, 50 milliliters of ether and 25 grams of ice,over a period of 15 minutes at zero to ten degrees centigrade. After allthe cyanogen bromide was added, the reaction mixture was stirred for tenminutes more. Ten milliliters of 40 degrees Be'. sodium hydroxidesolution were added to liberate the cyanamide from its hydrobromide. Thefree base was extracted with a total of 200 milliliters of ether, theether extract Washed with 25 milliliters of saturated sodium sulfatesolution and then dried over anhydrous sodium sulfate. After removal ofthe solvent, a practically quantitative yield, 20.5 grams, of N-(2-dimethylaminoethyl)--N- (benzyl) cyanamide was obtained as a paleyellow viscous liquid.

A solution of 20.3 grams (0.1 mole) of N-(2- dimethylaminoethyl) -N-(benzyl) -cyanamide :and five milliliters of triethylamine in 40milliliters of alcohol was saturated with hydrogen sulfide at tendegrees centigrade for a period of vtwo and one-half hours.v After thistime, crystallization started and within la few minutes the reactionmixture was substantially a solid mass of crystals. The reaction mixturewas allowed to stand at ve degrees centigrade for 24 hours and then thecrystalline mass was broken up, filtered olf, and the lter cake Washedwith alcohol. Several more crops of crystals were obtained onconcenv:trating the mother liquors bringing the total Example.tf-Preparation of N,N-dimethyl-N benzyl N (2 thz'azolyl)ethylenediamine monohydrochloride A mixture of 5.0 grams (0.021 mole) of1-(2- dimethylaminoethyl) -1- (benzyl) -Z-thiourea, '3.2 grams (0.021mole) of diethylchloroacetal Vand 3.6 grams (0.037 mole) of concentratedhydrochloric acid was heated at 100 degrees centigrade,

for one hour. Aftercooling thereaction mixture The absorption to 25degrees centigrade, ve milliliters of 40 degrees B. sodium hydroxidesolution were added to give a strongly alkaline solution. The basiccompound was extracted with a total of 30 milliliters of ether, theether extract Washed with live milliliters of saturated sodium sulfatesolution and then dried over anhydrous sodium sulfate. All the solventwas removed by distillation in vacuo. The remaining 5.5 grams of viscousliquid was converted to the monohydrochloride by dissolving it in amixture of five milliliters of anhydrous ethyl alcohol and twentymilliliters of ethyl acetate and subsequently adding a solution of 0.76gram (0.021 mole) of hydrogen chloride in 5.5 milliliters of anhydrousethyl alcohol. The mixture was heated to dissolve the crystallineprecipitate and then allowed to cool slowly. The crystalline product wasfiltered off, washed with ethyl acetate and -dried at fifty degreescentigrade. A second crop of crystals was obtained by concentrating thevmother liquors bringing the total yield up to 5.1 grams or 81.8 percentof the theoretical.

After recrystallization from twenty milliliters of n-butanol there wereobtained 4.6 grams of pure N,N-dimethyl-N -benzyl-N (Z-thiazolyl)ethylenediamine monohydrochloride, a ne light tan crystalline powder. Itmelted at 176-177 degrees centigrade and its absorption spectrum inmethanol showed a maximum at 264 mu. molecular extinction 8790 and aminimum at 230 mu. molecular extinction 2384.

Example 4.--Ereparation of N-(4-7nethoybenzyl) -Z-am'inoethanolNinety-one grams (1.5 mole) of 2-aminoethanol were added with rapidstirring during a period of five minutes to a solution of 204 grams (1.5mole) of methoxybenzaldehyde in 1500 milliliters of specially denatured3A alcohol at 25 degrees centigrade. After standing at room temperaturefor one-half hour, 4.0 grams of a palladium-carbon catalyst (fivepercent palladium) was added and the mixture agitated at 55-60 degreescentigrade under hydrogen at atmospheric pressure. After three hours,when the theoretical amount of hydrogen, 33.6 liters, had been absorbed,the solution was filtered and the alcohol removed by distillation. Theoily residue was distilled in vacuo and the fraction distilling at129-131 degrees centigrade at 0.26 millimeter collected separately. Thisfraction weighed 222 grams, and was found to be practically pure N- (4-methoxybenzyl)-2-aminoethanol having a specific gravity of 1.1016 at 25degrees centigrade, refractive index of ND25 1.5430 and a purity bypotentiometric titration to pH 5.0 of 99.5 percent. This compound may bereadily converted to the diamine derivative by reaction in aconventional manner with a suitable amine.

Example 5.-Preparation of N-(2-dimethylaminoethyl) -N-(4-methozlrybenzyl) -cyanamide zyl) ethylenediamine, 70 milliliters ofether and V35 grams of ice. during ay period of fifteen minutes at zeroto ten degreesgcentigrade After all the benzyl-Z-chloropropylaminehydrochloride were added over a period of minutes with rapid stirring toa mixture of 386 milliliters (2.0 mole) of percent aqueous dimethylaminesolution and 350 milliliters of alcohol maintained at 25 degreescentigrade. After the solution was clear, which required about fiveminutes after the last addition, it was allowed to stand at roomtemperature for 24 hours. The solution was concenti-ated to='200milliliters by distillation in vacuo and then cooled to 25 degreescentigrade. A saturated aqueous solution of 50 grams of sodium hydroxidewas gradually added and the free base extracted with ether. The etherextract was dried over potassium carbonate, the solvent removed bydistillation, and the oily residue distilled in vacuo. The fractiondistilling at 95-96 degrees centigrade at 3.0 millimeters was collectedseparately. This fraction weighed 48 grams, representing a iifty percentyield of pure N2,N2 dimethyl N1 benzyl 1,2 propanediamine. It is acolorless liquid having the following p-hysical properties: Specificgravity 0.9276 at 25 degrees centigrade, ND25 1,5010.

The dihydrochloride was prepared by adding the theoretical amount ofalcoholic hydrogen chloride to a concentrated solution of the base inanhydrous alcohol, adding ether and allowing the salt to crystallize outat five degrees centigrade. The resulting white crystalline N2,N2dimethyl-Nl-benzyl-1,2-propanediamine dihydrochloride melted at 172-173degrees centigrade and on analysis was found to contain 26.49 percentchlorine (theoretical 26.74 percent).

Example 11e-Preparation, of N2, N2-dimethyZ-N1- (4-methozcybeneyl) -1,Z-propanediamine One hundred and twenty-five grams(0.5 mole) ofN-(4-methoxybenzyl) 2 chloropropylamine hydrochloride was added over aperiod of fteen minutes with rapid stirring to a mixture of 386milliliters (2.0 moles) of 25 percent aqueous dimethylamine solution and375 milliliters of alcohol maintained at 25 degrees centigrade. Afterthe solution was clear, which required about 'five minutes after thelast addition, it was allowed to stand at room temperature for 24 hours.The solution was concentrated to 300 milliliters by distillation invacuo and then cooled to 25 degrees centigrade. A saturated aqueoussolution of fty grams of sodium hydroxide was gradually added and thefree base extracted with ether.

The ether extract was dried over potassium carlSpecii'lc gravity 0.9670at 25 degrees centigrade,

On potentiometric titration to pI-I 3.50 with standard hydrochloric acid97,4 percent of the Vtheoretical amount of acid was consumed,

The dihydrochloride was prepared by adding the theoretical amount ofalcoholic hydrogen chloride to a solution of the base in anhydrousalcohol, heating to obtain complete solution fof the precipitated saltand then allowing it to crystallize at room temperatre. The resultingwhite,

crystalline, N2,N2 dimethyl N1, (p methoxybenzyl) 1,2 propanediaminedihydrochloride Example 12.--Preparation of N-(Z-dimethylaminowomll) -N-(4-methoybenayl) -cycmamide Cyanogen bromide was prepared by graduallyadding a solution of 22.4 grams (0.33 mole) oi potassium cyanide inmilliliters of water to a mixture of 52.6 grams (0.33 mole) of bromineand 200 grams of ice. After standing for about ten minutes at zero tofive degrees centigrade, the resulting cyanogen bromide solution wasadded to a mixture of 73 grams (0.33 mole) of NRW-dimethyl-Nl-(li-methoxybenzyl) 1,2 propane diamine-175 milliliters ofether and 225 grams of ice, during fteen minutes atzero to five. degreescentigrade with constant stirring. After all the cyanogen bromide wasadded, the reaction mixture was stirred for one-half hour more and then3,4 milliliters of 40 degrees B. sodium hydroxide 4solution were addedto liberate the cyanamide `from its hydrobromide. The free base wasextracted with a total of 400 milliliters ofY ether. The ether extractwas washed with 50 milliliters of saturated sodium sulfate solution andthen dried over anhydrous sodium sulfate. After removal of the solvent,there remained 80 grams or a 98.5 percent yield ofN-(Z-dimethylaminopropyl) -N-(4-methoxybenzyl) cyanamide as a brightorange colored viscous liquid.

Example 13.--Preparation of I-(Z-dz'methyla-minopropyl) -1(r4-methofvybenzyl) -Z-thourea A solution of 80 grams (0.323 mole) ofN-(2- dimethylaminopropyl) N (4-methoxybenzyl) cyanamide in 120milliliters of alcohol and 40 milliliters of 28 :percent ammoniumhydroxide was saturated with hydrogen sulde at ten degrees centigradefor a period of six hours. The clear yellow reaction mixture was allowedto stand at five degrees centigrade for 48 hours and then the productwhich crystallized out was tered off, washed with alcohol and dried at50 degrees centigrade. Another small crop of crystals Was obtained byconcentrating the mother liquors bringing the total yield of the Whitecrystalline product up to 72 grams or '7 9 percent of the theoreticalyield. After recrystallization from alcohol, 66.9 grams or'a 73.7percent yield of pure. l-(2-dimethylaminopropyl)-1-(4 methoxybenzyD-Z-thiourea was obtained in the form of coarse white crystals meltingat 1075-1085 degrees centigrade.

Example .Z4-Preparation of N2,N2dimethyl-N1 (si-methozybenzyl) -N1-(i2-thiazolyl) -1,2 propanedamz'ne monohydrochloride Forty-six andnine-tenths grams (0.166 mole) of 1-(2-dimethylaminopropyl) 1(4-methoxybenzyl) -2-thiourea and 25.8 grams (0.166 mole) ofdiethylchloroacetal were mixed together at 25 degrees centigrade, 20.8milliliters (0.25 mole) of concentrated hydrochloric acid added and themixture stirred at -95 degrees centigrade'for one hour. The reactionmixture was cooled to 25 degrees centigrade, 40 milliliters of 40degrees B. sodium hydroxide solution added, and the base extracted witha total of 500 milliliters of ether. The ether extract was dried overanhydrous sodium sulfate and all the solvent removed by distillation.The light brown oily residue, which weighed 51.9 grams was dissolved in50 milliliters of anhydrous alcohol and a solution of 30,4 millilitersof alcoholic hydrogen chloride contairung doa grams. ioilu'mole) 'orhydrogen chloride added. All the solvent was removed by distillationunder vacuum and the residue ont??- tallized' from methylethyl ketone.The resulting pure NNzedimethrl-Nl.-(d-methoxybenzyl)Nif (faethiazcl'yl)1.2 nropanediamine monohydrochloride weighed 30.5 grains and melted at12.4- 12.5 degrees centierade.

Sulfur content 9.30 percent (theoretical. 9.38 Percent-l.

Example Iii-,Preparation of N-(A-dimcthoybenzyl) -Ztaminoethanol n 011e:hundred and thirty-six grams (0.82 mole) of veratraldehyde were added toa solution oi t2 grams (1.5. moles)- of 2-aminocthanol and 230milliliters of 90 percent fornito acid and the .resultins; mixturedistilled very slowly. .After ve. hours, the temperature of the reactionmixture had. reached i90- degrees centigrade. Distillatien was.continued ,for another three hours, the tern' perature finally reaching195 decrees oentielade. A. total of R18. milliliteis of distillate wasobtained, consisting mainly of forrnie acid, water, a little2-amiuoethanol and Ionly -a trace of veratraldehyde. The reactionmixture was allowed to stand overnight. at roomtempcrature andvthen asolution of. 40 milliliters of Water iny 1.75 milliliters ofconcentrated hydrochloric acid Was added. After heating at de-100degrees centigrade for one hour` the reaction mixture was cooled to 25degrees centigrade, diluted with 150 millliters of Water and extractedwith .25() milliliters of ether to remove unchanged yeratraldehyde andother ether soluble by-products. The ether extracted reaction mixturewas made strongly alkaline by the careful addition 0,1 170 grams `ofsolid potassium hydroxide and then extracted with several portions oyn-loutanol, using 400 milliliters in all. fvhe' n-butanol extract wasdried over anhydrous sodium sulfate, the solvent removed by distillationin vacuo at millimeters and the residue fractionated in vacuo at 0.5millimeter. The fraction distilling,` at 158-159 degrees cerltigjradewas collected separately. This fraction was found to be practically pureN(3,4dimethoxyhenzyl) -2- aminoethanol and weighed 94 grams,representing a yield of 54-.2 percent based on the veratraldehyde. Itwasv obtained as a colorless, viscous liquid which solidified to a whitecrystalline mass after standing at. room' temperature for 24 hours. Onpotentiometric titration to pH 5.1 with stand ard' hydrochloric acid,100.5 percent of the theoretical amount of hydrochloric acid wasoonsume'd.

The hydrochloride was prepared by adding the theoretical amount ofalcoholic hydrogen chloride to a concentrated solution or the .base inanhydrous alcohol, adding an equal volume of ether and allowing the saltto crystallizc.' .After drying in vacuo at 80 degrees centigrade overphosphor. ous pentoxide., the N-(SA-dimethoxybenayll-Ze aminoethanolhydrochloride, White, needle, shaped crystals, melted at 110411 degreescentigrade and on analysis was found to contain 14.37 percent oichlorine (theoretical 14.31 percent chlorine).

Example. l6..--Preporation of N(3.4-dimethoru bcneyl)-Z-chlorocthrlaminc hydrochloride A solution of 103 grams (0.49 mol-e)of Natrlldirmethonycenzyll, Zsaminoethanol- 'in 50.0' rnlli liters ofethylene dichloride maintained at. 30a-.e0 degrees centierade was.saturatedv with dry' hydrogen chloride with rapid stirring for a periodof one hour.. The. reaction s 'mixture' .then

'isr

1&4 warmed to degrcescentisrade and '71.5 grams (0.50 nucleil vofthlonyl chloride added dropwise over a period of five hours with rapid,stirring- The temperature Was allowed to rise gradually to about 73degrees centigrade at the completion of the addition ,of thionylchloride. The mixture Was stirred at73-'78 degrees centigrade foronehalf hour more, the heat then turned cil and the reaction mixtureallowed to stand overnight without'stirring. It vwas then concentratedto 250 milliliters by distillation, cooled to 25 degrees centigrado andthe crystalline product filtered off, The crystalline product was Washedwith ethylene dichlorde and 'then dried at 60 degrees centiarade.Another lsmall crop of cystalline material was obtained by concentratingthe mother liquors. bringing the total amount of crude product y up to11.41 grams, or an 87- percent yield.

216.68,v percent (theoretical 26.65 percent). f

Example 17.-Prepdation of` N,Ndz'methyZ-N- (3!4-dimethoxybenzg/Z)-ethylenedz'amine Seventy-nine and eight-tenths grams (0.3 mole) of N (3,4edirnethoxybenzyb2-chloroethylamine hydrochloride were addedportionwise over a period of fteen minutes, with rapid stirring, to amixture of 290 milliliters (1.5 moles) of 2.5 percent aqueousdimethylamine solution and 200 milliliters of alcohol. When the additionwas complete, the temperature was gradually raised to 60 degreescentigrade over 'a period of onehalf hour, held at'this point for one'hour more and the reaction mixture concentrated to Irrilliliters bydistillation in vacuo.. The concentrat/ede ,reaction mixture was cooledto 25 degrees centigrade and a saturated aqueous solution of 35 grams'ofsodium hydroxide added gradually with constant stirring and cooling in awater hath. The mixture Was extracted with 600 milliliters of nehutanol,the ifi-butanol extract washed with 25 milliliters of saturated sodiumsulfate solution and then dried over anhydrous sodium tilllate. Thesolvent was removed by distillation in vacuo.' The light-brown, oilyresidue which resulted was dissolved in ll0() milliliters of ether andltered from the resinous precipitate.

The ether was removed by distillation and the nale yellow oily residue,68.6 grams, distilled in vacuo. The fraction d istilling at 126.5 to127.5 degrees centigrade at 0.3 millimeter was collected separately.This fraction was found to be pure NN dimethyl-N e(3,4-dimethoxybe1izyl) -ethylorlodiamine and weighed 58.5 grams which isan 31.9 percent yield based on the Nf(3,4-dimethoxybenzyl)-2chloroethylamine hydrochloride used. It is aclearl colorless liquid having the following physical properties:Specific gravity 1.0322 at 25 degrees centigrade, Nuff 1.5222.

Purity by potentiometric titration to pH 3.78 with hydrochloric acid wasfound to be 99.7 percent.

The dihydrochloride was prepared hy adding the theoretical amount ofalcoholic hydrogen chloride to. a solution of the. base in anhydrousalcohol. .Alter recrystallzing thenrecipitated dihydrochlorideiromalcohol .it melted at 2,15-2155 degrees centigrade.

Analysis of the dihrdroehloride of, Niacimethyl- N e (3Adimethoxrbenzrll e ethyler1eattacca 15 diamine yielded: carbon 49.89percent (theoretical 50.16 percent), hydrogen 7.81 percent (theoretical7.77 percent), nitrogen 8.88 percent (theoretical 9.00 percent),chlorine 22.75 percent (theoretical 22.79 percent).

Example 18.--Prepa1ation of N-(Z-dimethylaminoethyl) N(3,4-dimethoxybenzyD-cyanamide Cyanogen bromide was prepared bygradually adding a solution of 13.6 grams (0.2 mole) of ptassium cyanidein 50 milliliters of water to a mixture of 32 grams (0.2 mole) ofbromine and 100 grams of ice. After standing for about fifteen minutesat zero to five degrees centigrade, the resulting cyanogen bromidesolution was added over a period of fteen minutes to a mixture of 47.7grams (0.2 mole) of N,Ndimethyl-N(3,4- dimethoxybenzyl) ethylenediamine,150 milliliters of ether and 150 grams of ice maintainedl at atemperature between zero and 'live degrees centigrade with constantstirring. After all the cyanogen bromide was added, the reaction mix#ture was stirred for one-half hour more and then 32 milliliters of 40degrees B. sodium hydroxide solution was added to liberate the cyanamidefrom its hydrobromide. The free base was extracted with a total of 500milliliters of n-butanol. The n-butanol-ether extract was washed with 25milliliters of saturated sodium sulfate solution and subsequently driedover anhydrous sodium sulfate. After removal of the solvent bydistillation in vacuo, there remained 49.4 grams of a 94 percent yieldof N-(Z-dimethylaminoethyl) N (3,4 dimethoxybenzyl)-cyanamide as a paleyellow viscous liquid.

Example 19.-Preparati0n of 1 (2 dimethylamznoethyl) 1 (3,4dimethozcybeneyD-Z- thiofurea A solution of 49.4 grams (0.188 mole) ofN-(2- dimethylaminoethyl) N (3,4 dimethoxyben- Zyl) -cyanamide in 80milliliters of alcohol and 25 milliliters of 28 percent ammoniumhydroxide was saturated at a temperature of five to ten degreescentigrade with hydrogen sulfide for a period of two and one-half hours.The reaction mixture was allowed to stand in the refrigerator overnight,after which time all the solvent was removed by distillation in vacuo.The residue was mixed with 50 milliliters of benzene and the mixtureagain distilled to remove the last traces of water. After dissolving theresidue in 150 milliliters of anhydrous alcohol, 25 milliliters ofanhydrous ether were added and the solution a1- lowed to stand in therefrigerator to crystallize. After 24 hours the crystalline product wasFiltered off, washed with ether and dried at 50 degrees centigrade.Another small crop of crystals was obtained by concentrating the motherliquor, bringing the total yield up to 47.7 grams, or 85.5 percent ofthe theoretical. After recrystallizing from anhydrous alcohol, 41 gramsor a 73.5 percent yield of pure 1-(2-dimethylaminoethyl)-1-(3,4-dirnethoxybenzyl) -2-thiourea was obtained in the form of a iine,light buss, crystalline powder melting at 107.5-108 degrees centigrade.On analysis it was found to contain 10.71 percent of sulfur (theoretical10.78 percent sulfur).

Twenty-nine and seven-tenths grams (0.10 mole) of 1 (2dimethylaminoethyl) 1 (3,4-

dimethoxybenzyl) -2-thiourea andv '15.5 "grams (0.10 mole) ofdiethylchloroacetal were mixed together at 25 degrees centigrade. 12.5milliliters (0.15 mole) of concentrated hydrochloric acid were thenadded over a period of five minutes with constant stirring. The reactionmixture was stirred at 90-95 degrees centigrade for two hours. It wa-sthen cooled to 25 degrees centigrade, 25 milliliters of 40degrees B.sodium hydroxide solution added and the mixture extracted with 350milliliters of ether. The ether extract was dried over anhydrous sodiumsulfate, and all the solvent removed by distillation. The brown, oilyresidue, which weighed 31.8.grams, Was dissolved in 2O milliliters ofspecially denatured 2B anhydrous alcohol and 19.8 milliliters ofalcoholic hydrogen chloride containing 3.65 grams (0.10 mole) ofhydrogen chloride added, followed by milliliters of 99 percent ethylacetate. The solution was allowed to stand at ve degrees centigrade forabout sixteen hours, then the crystallineproduct was ltered off, washedwith ethyl acetate and dried at 50 degrees centigrade. Two more crops ofcrystals were obtained by concentrating the mother liquors, bringing thetotal yield of crude product up to 21.3 gramsor 59 percent of theory.After recrystallization from a mixture of ethyl acetate and anhydrousalcohol in the ratio 2:1, the pure N,N-vdimethyl-N(3,4 dmethoxybenzyl) N(Z-thiazolyl) -ethylenediamine monohydrochloride was obtained as fine,light tan crystals melting at 149-150 degree-s centigrade, corrected. V

Analysis: Sulfur 8.94 percent (theoretical 8.96 percent).

Eample 21.-Preparation of N-(4-chlo'roben- Zyl) -Z-amz'noethanol Fourhundred and twenty grams (B0-moles)- of 4-chlorobenzaldehyde was addedto a mixture of 366 grams (6.0 moles) of Z-aminoethanol and 790milliliters (15.5 moles) of percent formic acid. The mixture wasdistilled slowly over a period of eight hours. During this time, about535 milliliters of a mixture of water and formic acid distilled over andthe temperatureof the reaction mixture gradually -rose to 200 degreescentigrade. After this temperature was reached, practically no moredistillate was obtained. The heat was turned off, the reaction mixturecooled to 25 degrees centigrade, 700 milliliters of concentratedhydrochloric acid and 200 milliliters of water added and the mixtureheated to 100-105 degrees centigrade for one and one-half hours. It wascooled to 25 degrees centigrade, diluted with 200 milliliters of waterand extracted with 800 milliliters of benzene to remove acid insolubleby-products. The mixture was then made alkaline by the addition of 1350milliliters of 40 degrees B. sodium hydroxide solution and the liberatedbase extracted with ether. The ether extract was washed with water,dried over anhydrous potassium carbonate and all the solvent removed bydistillation. The oily residue was distilled under vacuum and thefraction boiling at 106-108 degrees centigrade at 0.12 millimetercollected separately. This fraction weighed 368 grams and was found tobe practically pure N (4 chlorobenzyl) -2-aminoethano1, a colorlessviscous liquid, specic gravity 1.1810 at 25 degrees centigrade, ND251.5540, chlorine by analysis 19.06 percent (theoretical 19.10 percent).

The hydrochloride of the base was prepared as follows:

Thirty-seven grams of the base were dissolved in- 50 milliliters- 'ofanhydrousA ethyl alcohol' and.'

32imillilitersof aleoholicfhydroohloric acid (100 milliliters=v2313grams-Emi added.. 'lhemixture` ent as-y HC1- salt 16-.04- percent(theoretical 15.96

pereent) tillation. The -eilywnesdue wasA distilled underf Vacuum and.thetf-iacti'on distilling. at 80s-.81- degrees centgradoand 0*.05.millimeter collectedl separately This fractionv weighed 259. gramsZ-reTiZorQotii'Jlomifte-z hydroehloride;

'Aiso1ntionoff325' grains. (1,75.. moles.) of. Iii-14e ohlorohenzyl)-2aminoethanole in.l ZiOO'niiililiters of, .ethylene -diohloriiiesaturatedwitnldry bye.. drogen, chloride while stirring rapidly atgtfe.degrees. eentigraole The mixture Was then heated to, 16D degreesoentigrade and. the. drop- Wise addition oi'ZQ. grams (2.1K moles)ofitnionyl. chloride: started.. The. temperature was grad.,- uallyincreased, so. that. aty the end of'. two. novas the. reaction mixturewas boiling, gently. The

adtltionof the .tliioi'nzly Chloride red.' ed. a total. of.. meneurs...Stirrinaatreilux, temperatnrewas contirnied.y for two.; hours.longer,lthen. the, heat wasQturned, 0lltl;\e stirrer stopped, and theTenotionlmixture, allowed. to .stand overnight. The.

exness.. thionyl .chloride was, removedy by distillation-and the.reaction mixture concentrated. to about 1.50.0., milliliters... greeecentigradegthe .crystalline nrodnet filtered oi, Washed Witnethylene.diehloride and dried at. 5ft degrees. oentigrade... Another small erop.o i crystals. was.k obtained. by eonoentratine. .thev mother liquor toabout 3040,l rnilv.,iters. 339th. crops of crystals, 383 grams in all,were combined and` 'reorystalliaed.- frein.- 2590 millilters. ofspecially denatured. .3A aloohol.. 'linev reerys'tallized productN-(l-chlorobenzyl) -Z-chloroethylamine hydroonloride weighed 3.55eramsi. .twas obtained; as a White crystalline: powder- Melting,ypoint.vv 2li-6:2171 degrees cantiere-de eo.:-` rented Analysis: Totalchlorine.- 4-3.90. percent.. (theoE retiaal'ie22fnereent) .Chlorine.present ,HSL ysalt 114-79. neroent, (theoretical.liilxaneneent)y..Exemple 2te-Preparation .Off NiNed'imethi/FN 41-ehlorobena1/Il)-ethy'leneoiiamine "Three hundred and: twentyfonegrams (13.31 molesoffN-(ilichlorobenz-yli) -m2 e chloroeth-yli-s. aminehydrochloridewas;yadded portionwise,

Itwas oooled to 2o cle.- f

during-'ten minutes, with rapid stirringi to amtxtureet L200 milliliters(r3.361 moles offaoueousy dmethylamine solution and 250-fmillilters ofalcohol. At the start the `reaction mixturewas-at 25 degrees-oe-ntignadebut fifteen minutes after the addition` was'complete rthe temperature-Was- 45 degrees (sentia-rade. Stirring-=was discontinued: and;the-o1ear4reaction mixture allowed vto stand at roomtempera-ture for l-ly hours.It was thencdrieenifrated to -l-G -rn-illili-ters by.- distillationunder Vacuum. The concentrated solution Wasv cooled: to 25- degreescentg-rade andthe baseliberatect bythe addition Vof 309- rnillilitersoff' 40:

degrees B.sodiurn hydroxide solution. The was lextracted with two; 15dmilliliter; *portions* of ether, the extranetV dried overanhydrouspotas- `slum carbonate and the solvent removed-by-disgradeandfthen .20.frniliiit.

sodium; hyditQXide-solntionwas adrieditoliberate,

representingLelli?,v percent yieldiof N,N.-dimethylN(p'ch1orobenzy1)-ethylenediamine.. It is a clean colorless liquidihaving thel followingA physicalupropentiess Specific;- gra-yityf.1"05191` at 25 de.

greesicentignade,NDZLZlD:

Analysisz- Chlorine 16173: 'percent (theoretical lflzpereentll.

The .dihydrochloride was` prepared by yadding the theonetioali amount.off alcoholic hydrogen chloride toyal ten percent solution offthe basein` anhydrous alcohol; heating them-ixtureto dissolve the precipitated-vsalt' and: allowing it tov crystallizeeat roorntemperature.l Afterrecrystalli'z-ation from, anhydrous .-alcohol, they N,l\l di. methylnldfeidg-chlorobenzm -ethylenediamine dihydroeiiloririe. was.: obtained. theform of.

White..` :matted needles melting.l at'. '2410.12.11V ie greescentigradecorretedz.

Analysis of the vdhydrochloride: Chlorine presentes the dihydteehleridesait 2i.69;ner.eent theo..retinal` ,.nnereent).

Total -oniorine 3.6.30:neree t (theoretioal 35i-2e percent),

`.Cianoeen bromide,-

nrenaifed by,- eradualiy adding asolntieni-nt 7822 trains ill-.1infiolesi` er".

95. nement, potassium. eyanideinl .1;5Qv miil'iliters- Zero. to. nwedegrees.; @enterada with constant- Stiilllea .atten all.. the eyanegenvbromide. was., adieiillie tioniinix ure, Wasfstirredlior. .ni-f

elfe.. of, .40, .degrees B.

the .cyanarnide fromitahydroorornide.- The. free base.. Wasentraetedwith] va..t. .ift..a.1 of- 120.0 milite iitersot etiienI tneeilierextract washed with 5.0 miililiters; 0i saturated sodium sulfatesolution and,- tlienaried over. aniivldrious sodium saltate Aiter.temoxcalloitliesolyent there remained 2,43` grams .or a. 98 ereentyieldl of iii- @dimethylamineethylieNf-ii-snliorqtenayl).osianarnisie.asa viseonsiorange-oo1oredlionid,.

benzyl) -cyanamide A solution. of.: 24e grains.-tliia;moles-)1` oi. N42-dimethylamnoethyl?" lorobenzyl) -cyanamide and 40 grams of anhydrousammonia in odmilliliters A@i percent' alcohol: was` satuirated:with.hydrogensulfideat vetotten degrees other smallI crop ofcrystals #was obtained lby oon-v centratngthe motherlliquorgbringingthev total yield3 ot crudeproduet up to- 259f'grams or 92pereenit of# the theoretial yield. rec-rystal-lization from.V alcohol;the. v142--dimet/11511- mofa/ie,degreesi centi:V

19 aminoethyl) -1- (4-chlorobenzyl) -2-thiourea was obtained in the formof fine white crystals melting at 119-120 degrees centigrade corrected.

Analysis: Sulfur 11.82 percent (theoretical 11.80 percent). Chlorine12.93 percent (theoretical 13.05 percent).

The hydrochloride was prepared in almost quantitative yield by addingthe theoretical amount of alcoholic hydrogen chloride to a 20 percentsolution of the base in anhydrous alcohol and allowing the solution tostand in the refrigerator for four hours toy crystallize. Thehydrochloride of 1-(2-dimethylaminoethyl) -1-(4- chlorobenzyl)2thioureawas obtained in the form of ne white crystals melting at 177-1775degrees centigrade corrected.

Analysis of the hydrochloride: Sulfur 10.40 percent (theoretical 10.40percent). Total chlorine 22.91 percent (theoretical 23.00 percent).

Example 26.--Preparation of N,Ndimethyl-N (4 chZorobeneg/Z)N(2thz'azolyl) -ethyle'nediamine monohydrochloride Two hundred andtwenty-two grams (0.70 mole) of 1- (2-dimethylaminoethyl)-1-(4-chlorobenzyl) -2-thiourea hydrochloride, 89 grams (0.70 mole) of98 percent dimethylchloroacetal and 60 milliliters of concentratedhydrochloric acid were mixed at 25 degrees centigrade and then stirredat 75-82 degrees centigrade for two and one-half hours. The reactionmixture was cooled to 25 degrees centigrade, `210 milliliters of 40degrees B. sodium hydroxide solution added and the base extracted with atotal of 900 milliliters of benzene. Thel benzene extract was washedwith two 50-milliliter portions of saturated sodium sulfate solution andthen dried over anhydrous sodium sulfate. The dry benzene extract wasdiluted to 1000 milliliters with dry benzene and a solution of 25.6grams(0.70 mole) of anhydrous hydrogen chloride in 100 milliliters ofanhydrous alcohol added with stirring during ten minutes. The solutionwas allowed to stand at iive degrees centigrade for several hours `tocrystallize. lThe crystalline product was ltered off, washed withbenzene and dried at 50 degrees centigrade. On concentration of themother liquor, three more small crops of crystals were obtained makingthe total yield of crude product 229 grams or 98 percent of thetheoretical amount.v After recrystallization from npropanol there wasobtained 205 grams or an 88 percent yield of pure N,Ndimethyl-N'(4chlorobenzyl) N (2 thiazolyl) ethylenediamine monohydrochloride in theform of a ne, light tan crystalline powder melting at 156-157.5 degreescentigrade corrected.

Analysis: Sulfur 9.59 percent (theoretical.9.65 percent). Total chlorine21.15 percent (theoretical 21.34 percent).

Example 27.-Prepa1'ation of N-(Z-thenyl) -2 aminoethanol A mixture of140 grams (1.25 moles) of 2- thiophenealdehyde, 153 grams (2.5 moles) of2- aminoethanol and 350 milliliters of ninety per-r cent formic acid wasdistilled very slowly. The Z-thiophenealdehyde which distilled over withthe iormic acid and water was separated at intervals and returned to thereaction mixture. As the distillation progressed, the temperature of thereaction mixture gradually rose, reaching 176 degrees centigrade at theend of eight hours. The reaction mixture was allowed to cool to 25degrees centigrade, 250 milliliters of concentrated to 105 degreescentigrade for two hours.

hydrochloric acid and 200 milliliters of water added and the resultingsolution heated to It was cooled to room temperature, diluted with 200milliliters of water and extracted with benzene to remove unchanged2-thiophenealdehyde and other benzene soluble impurities. The benzeneextracted acid solution was stirred with decolorizing carbon, nlteredand then made strongly alkaline by the addition of 500 milliliters of 40degrees B. sodium hydroxide solution. The oily base was extracted withn-butanol, the extract dried over anhydrous sodium sulfate and thesolvent removed by distillation until the vapor temperature reached 45degrees centigrade at 30 millimeter pressure. The crude residual productwhich weighed 152 grams was purified by distillation under vacuum. Thefraction distilling at 34-85 degrees centigrade under 0.14 millimeterpressure was collected separately. The pure N- (2-thenyl)-2-aminoethanolweighed 113 grams and was obtained as a colorless, viscous liquid.

Specic gravity 1.1673 at 25 degrees centigrade, refractive index ND251.5900, sulfur content 20.23 percent (theoretical 20.33 percent).

The hydrochloride was prepared by adding 2.5 milliliters of alcoholichydrogen chloride (0.016 mole) to a solution of 2.35 grams (0.015 mole)of the pure base in vevmilliliters of ethylenedichloride. The mixturewas heated to boiling and anhydrous alcohol added dropwise untilsolution was complete. After standing in the refrigerator for two hours,the crystalline product was 'filtered oii and recrystallized from amixture of ethylenedichloride and anhydrous alcohol. PureN-(2-thenyl)-2-aminoethanol hydrochloride was obtained in the form ofwhite needles, melting at 84-85 degrees centigrade,

Sulfur content 16.46 percent (theoretical 16.55 percent). Chlorinecontent 18.29 percent (theoretical 18.31 percent).

Example 28.-Prepa1atz'on of N-(Z-thenyD- Z-ChZO/methylaminehydrochloride A solution of grams (0.7 mole) of N-(2- thenyl)-2-aminoethanol in 1200 milliliters of ethylene dichloride was saturatedwith `dry hydrogen chloride while stirring rapidly at 35-40 degreescentigrade, The mixture was then heated to '60 degrees centigrade andthe dropwise addition of 100 grams (0.84 mole) of thionyl chloridestarted. The temperature was gradually raised so that at the end `of twohours the reaction mixture was boiling gently. The addition of thethionyl chloride required ve hours. Stirring at reflux temperature wascontinued for two hours longer, then the heat was turned 01T, thestirrer stopped, and the reaction mixture allowed to stand overnight. Itwas then concentrated by distillation to reduce the volume to 500milliliters. The mixture was cooled to 20 degrees centigrade, thecrystalline product ltered 01T, Washed with ethylene dichloride Iand`dried at 50 degrees centigrade. Another small `crop of crystals wasobtained by concentration of the mother liquor to about 200 millilitersbringing the total yield of crude product up to 139 grams. The crudeproduct on recrystallization from specially denatured 2B anhydrousalcohol yielded 106 grams of pure N-(2-thenyl)2chloroethylaminehydrochloride melting at 156-157 degrees centigrade.

Analysis: Chlorine 33.43 percent (theoretical 33.43 percent), sulfur15.00 percent (theoretical 15.11 percent).

tig'rade corrected. The yield of pure product was Example 33t-Preparation of 5-br0mo-2-thenyl chloride no -CH A mixture of 122 grams(0.75 mole) of 2- bromothiophene and 70 milliliters ofconcentratedhydrochloric acid was stirred rapidly at zero to livedegrees centigrade and a rapid stream of Adry hydrogen chloride passedin while 75 milliliters (1.0 mole) of 36 percent formaldehyde solutionwere added dropwise during two hours. Stirring and addition of dryhydrogen chloride at zero to five degrees centigrade were then continuedfor three hours more. The reaction mixture Was diluted with 200milliliters of water and ice, extracted with 200 milliliters of ether,and the ether layer separated, washed with three percent sodiumbicarbonate solution, dried over anhydrous sodium sulfate, and the etherremoved by distillation. The oily residue weighed 156 grams and analysisproved it to contain 130 grams (82 percent yield) of 5-bromo-2-thenylchloride and a small amount of unchanged 2-bromothiophene. The crudeproduct was not puried but used directly for the preparation of-bromo-2- thenyl-2-aminoethano1.

Example 3'4.-Preparation of N-(5-bromo-2- thang/Z) -2-amz`noethanol Onehundred and fifty-six grams of crude 5- bromo-2-thenyl chloridecontaining 130 grams (0.615 mole) of the pure compound was addeddropwise to a mixture of 321 grams 5.26 mole) of 2-aminoethanol and 100milliliters of specially denatured 3A alcohol, which was previouslywarmed to 65 degrees centigrade. The rate of addition was regulated sothat the reaction temperature remained a-t 65-70 degrees centigrade;

about one and one-quarter hours being required V for the addition. Thereaction mixture wasallowed to stand overnight and then distilled under-30 millimeters pressure to remove the alcohol. The residue was mixedwith sufcient concentrated hydrochloric acid (about 105 milliliters) tobring the pH to 3.5 and extracted with 200 millliters of ether to removeacid insoluble by-products. It was then mixed with 60 milliliters of 40degrees B. sodium hydroxide and again extracted with ether. The etherextract was washed with 50 millilitersof saturated sodium sulfatesolution, dried over anhydrous sodium sulfate and all the solventremoved by distillation. The crude product weighed 125 grams and waspuried by distillation under vacuum. The fraction distilling at11S-114.5 degrees centigrade under 0.16 millimeter pressure wascollected separately. It was obtained as a colorless Viscous liquid andfound to be practically pure N- (5-bromo-2-thenyl) -2-aminoethanol.

Specific gravity 1.5482 at 25 degrees centigrade,

refractive index N1325 1.5580, bromine contentv 33.53 percent(theoretical 33.84 percent), sulfur content 13.49 percent (theoretical13.58 percent).

The hydrochloride of the base was prepared by adding the theoreticalamount of alcoholic hydrogen chloride to the base and adding ether toIprecipitate the hydrochloride. After recrystalmatted needles.

Melting point 131.5-1325 degrees centigrade. Sulfur content 11.73percent (theoretical 11.76 percent). Analysis based on total halogencontent 100.36 percent.

Emample 35. Preparation of N- (5-bromo-'2- thenyl)-Z-chZoroethyZ-I-amz'ne hydrochloride `A solution of 103.8 grams (0.44mole) of N-(5- bromo-Z-thenyl)-Z-aminoethanol in 700 milliliters ofethylene dichloride was saturated with dry hydrogen chloride whilestirring rapidly at 35-40 degrees centigrade. The mixture was thenheated to 60 degrees centigrade and the dropwise addition of 63 grams(0.53 mole) of thionyl chloride started. The temperature was graduallyraised so that at the end of two hours, the reaction mixture was boilinggently. The addition of the thionyl chloride required four and one-halfhours. Stirring at reflux temperature was continued for two hourslonger,'then the heat was turned off, the stirrer stopped and thereaction mixture allowed to stand overnight. It was then concentrated bydistillation to reduce the volume to 300 milliliters. The mixture wascooled to 25 degrees centigrade, the crystalline product filtered olf,washed with ethylene dichloride and dried at 50 degrees centigrade.Another small crop of crystals was obtained by concentration of themother liquor to about 50 milliliters, bringing the total yield of crudeproduct to grams. The crude product on recrystallization from speciallydenatured 2B alcohol, yielded 105 grams of pure N (5- bromo-2-thenyl)-2-chloroethyl-1-amine hydrochloride melting at 167-168 degreescentigrade corrected. I

Analysis based on total halogen 99.58 percent. Sulfur content 10.94percent (theoretical 11.02 percent).

Example 36.-Preparation of N,Ndz`methyl-N'- (5-bromo-2-thenyl)-ethylenedz'mine Eighty-seven and one-half grams (0.3 mole) of N (5bromo-2-thenyl) -2-chloroethyl-1-amine hydrochloride was addedportionwise, over a period of fifteen minutes, ywith rapid stirring to amixture of 275 milliliters (1.5 moles) of aqueous dimethylamine solutionand 275 milliliters of speciallydenatured 3A alcohol. At the start, thereaction mixture was at 25 degrees centigrade, butk 20 minutes after theaddition was complete the temperature was 45 degrees centigrade.Stirring was discontinued and the reaction mixture -allowed to standovernight at room temperature. It was then concentrated to about 300milliliters by distillation under vacuum. The concentrated solution wascooled to 25 degrees centigrade and the base liberated by the additionof 60 milliliters of 40 degrees B. sodium hydroxide solution. The basewas extracted tions of ether, the extract dried over anhydrous potassiumcarbonate and the solvent removed by distillation. The oily residue wasdistilled under grees centigrade, refractive index ND25 1.5470

with three milliliter por- -ethylenediamine It is a Analysis.: Broniine30.47 percent (theoretieal'id percent), sulfur 12.08 percent(theoretical 112.18 percent).

The dihydrochloride was prepared by adding the theoretical amount ofalcoholic hydrogen chloride to a seven percent solution of the base inspecially denaturec'iv 3A alcohol, heating the mixture to dissolve theprecipitated salt and allowing it to crystalli'ze at room temperature.The crystalline product was altered on, washed with specially denatured3A alcohol, and dried at 5o degreesL-centigrade. The resulting pureINN-'dimethyl-N'-(5-bromo-2-thenyl) ethylenediamine dihydrochloridewasobtained in the forro of white needles melting at 220221 degreescentigrade corrected.

Analysis of the dihydrochloride': Analysis based on total halogen 99.94percent, sulfur content 9.48 percent (theoretical 9.54 percent).

amp'lc .3l-Preparation of N- (Z-dimettyZaminoethyll) -N-(-bromo-Z-thenyl) -cydnamide Cyanog'en bromide was prepared by graduallyadding a solution of 18.5 grams (0.27 mole) of '95 percent potassiumcyanide in 40 milliliters of Water to a mixture of 48.2 grams '(0.27mole) of bromine 'and 150 vgranrs of ice. After 'standing for aboutten'minutes at zero to five degrees centigrad the resulting 'cyanogenbromide solution was added to a 'mixture of 65.7 grams (0.25 mole) ofN,Ndimethyl-'N- (Ei-bromo-z-thenyll -ethylene'damirie.1 200millliliter's' of ether and v15'() grams of ice during iiften minutes atzero to five degrees centigrade with constant stirring. After all; thecyanog'en bromide was added, the reaction mixture was stirred Iforfifteen .minutes longer at zero to live degrees centigrade and thenmilliliters of degrees Be. sodium hydroxide solution was added toliberate the cyanamide from its hydrobromide. The fre-e base was'extracted with ,a total of 3-50 milliliters of ether, the ether extractwashed with 25 millilitersl of saturated sodi'urn sulfate solution andthen dried over anhydrous sodium sulfate. After removal of the soil/entby distillation, there remained 71 .grams or a 98.4' percent yield ofN-(Z-dimethylaminoethyl) -N-(-bromo-Q-thenyl) -cyanamide as a lightyellow oily liquid which solidified to a light tan crystalline mass onstandingr in the refrigerat'or for 2'4 hours. The crystalline productwas found to have 'a melting point of 40-'41 degrees. centigrade.

Example 38.-Preparationof I-(Z-dz'm'ethylaminoethyl) -1(5-bromo-2-thenyl) -Z-thz'ourea A solution of '71 .grands (0.246 mole)ofN-(Z- dimethylaminoethyl.) YN (-5 bromo-2-thenylf) cyanamide andl tengrams of anhydrous ammo*- nia in -200 .milliliters of speciallydenatured 3A alcohol was saturated with hydrogen sulfide at five to tendegrees centigrade dur-ing two and one-half hours. The 'thickcrystalline suspension was allowed to stand at ve degrees centigrade for24 hours and then the crystalline product filtered off, washed with coldalcohol and vdried at degrees centigrade. The yield of crude product was73 grams or 92.3 percent of theory. After recrys-tallization Ifrom'anhydrous alcohol, 66.5 grams or an 81.7 vperce-nt yield of pure1-(2-dimethylaminoethyl) l1--(5bromoe2 thenyl 2thiourea was obtained asfine white crystals melting at 95.5-96Y.8' degrees centigrade.

Analysis: Broinine 24.69 .percent (theoretical 24.79 percent), sulfur19.822.1oereent (theoretical 19.89 percent).

The hydrochloride was prepared in almost qualitative yield "oy addingthe theoretical amount of alcoholic hydrogen chloride to a 2.5 per-centsolution of the base in anhydrous alcohol and allowing the solution tostand at live degrees Icentig'raole for 24 hours to cryetallize. Thehydrochloride ot 1 (Z-dimethylaininoethyl)v1-(5-brolno-IZ-thenyl)-2-thiourea was obtained in the form of lineWhtecrystals melting at 173- 74 degrees lcentigrade corrected.

Analysis of the hydrochloride: Sulfur 17.89

percent (theory 17.87 percent).

A mixture oi"v 57.4 grains (6.16 mole) of 1-(2- dimethylaminoethyl) l('5-bromo-2-thenyD- .Z-thiourea hydrochloride, 20.3 grams (6.16 mole) of98 percent dirnethylcholoroacetal and 18.6 inilliliters (0.16 mole)y ofconcentratedI hydrochloric acid was stirred at '75-80 degrees centigradefor two and one-quarterv hours. The reaction mixture was' then cooled to25 degrees centigrad'e, diluted with 30 milliliters of water, madealkaline with 35 milliliters of 40` degrees Be. sodium hydroxidesolution and the oily base extracted with 250r milliliters of benzene.The oenzerrel extract was' washed with 5() milliliter's of saturatedsodium sulfate solution, dried over anhydrous sodium sulfate andfiltered. The clear filtrate was mixed with 31.4 milliliters ofalcoholic hydrogen chloride containing 5.7 grains (0.157 mole.) ofhydrogen chloride and` allowed to stand at .five degrees centigrade-orabout lil-hours. The crystalline product was filtered off, washed withbenzene "andv dried at odegrees centigrade. Two more small vcrops' ofcrystals were obtained by c'omentraurig the mother nouer', bringing thetotal yield of crude productv up' to 55.3 grams or 90.12 percent oftheory. After 'recrystalli'zing from a mixtureof norm-a1 propanol and 99percent ethyl* acetate, the pure N,Ndimethyl-N (5 broro2thenyl-)-N(2-thiazolyl) -ethylenediamine monohydrochlorid'e was obtained as afine, light tan crystalline powder melting at 166- 16'?I degreescentigradej.

Analysis: Sulfur '16.64 percent (theoretical 16.75 percent).

A solution of. l44 grams @.591 mole) of sodium hypochlorite '421miliiiiters of water was added to a mixture lof 3952 grains (0.59 mole)of potassium cyanide; 700 grams of ice and 1D0 milliliters (11.2 xnoles)of concentrated hydrochloric acid with ycontinuous stirring over aperiod of ten minutes. To the resulting 'solution Aof cydnogenvchloride, was added rapidly' with stirring., 10d grams (d5 mole) ofN,Ndimethyl-N" (p-niethoxybenoyl)-ethylenediamine. After the addition.,stir-ringswars` continued for ve minutes. longer then' asoiution'of 60grams f( 1.5 moles) of sodium hydroxide in' 100 miliiliters or water wasa dadi The free' base' was extracted with 3Go milliliters of ether,thefeth'er extract washed with saturated sodium sulfate solution anddried over anlnfdrous sodium-sulfate. After removal of 'the solvent bydistillation there remained 99.7 grams of N (2dimethylaminoethyl)'-N-(pmethoxybenzyl-#cyanamide as a light orangecolored liquid on analysis was found to haye a ,purity oi 861 percent.

27 Example 41,-P1eparatzon of N-(Z-dimethylaminoethyl) (p-methoybeneyl)-cyanamide A solution of cyanogen chloride was prepared by passing 244grams (3.4 moles) of chlorine into a suspension of 224 grams (3.4 moles)of 99 percent potassium cyanide in 820 milliliters of ethylenedichloride and 24 milliliters (0.4 mole) of acetic acid over a period ofabout three hours at zero to ve degrees centigrade. The resultingcyanogen chloride was then distilled directly into a mixture of 550grams (2.42 moles) of 95 percent N,N dimethyl-N-(p-methoxybenzyl)-ethylenediamine and 1800 milliliters of water at ve to fifteen degreescontigrade with constant stirring. The addition of cyanogen chloride Wascontinued until the reaction mixture was at pil-I 6.5 and a slightexcess of cyanogen chloride was present. stirring was continued forone-half hour longer, then the resulting `cyanamide was liberated fromthe hydrochloride by the addition of a solution of 125 grams of sodiumhydroxide in 200 milliliters of water. The oily product was extractedwith 1000 milliliters of benzene, the benzene extract washed with asaturated solution of sodium sulfate and then dried over anhydroussodium sulfate. On removal of the solvent by distillation there remained561 grams of N- (2 dimethylaminoethyl) -N-(p-methoxybenzyl) cyanamide asa light orange colored liquid. It was found to have a specic gravity of1.0440 at 25 degrees centigrade. a refractive index of ND25 1.5260 and apurity of 91.5 percent determined by potentiometric titration to pI-I6.9.

Example 42.-Preparatz'on of N-(Z-dimethylaminoethyl) -N-(p-methoxybenzyl) -cyauamz'de A solution of cyanogen chloride wasprepared by passing 244 grams (3.4 moles) of chlorine into a suspensionof 244 grams (3.4 moles) of 99 percent potassium cyanide in 1100milliliters of ethylene dichloride and 15 milliliters (0.25 mole) ofacetic acid over a period of five =hours at Zero to five degreescentigrade. The resulting reaction mixture was then added to a solutionof 696 grams (3.22 moles) of 96 percent N,N-di methyl N' (pmethoxybenzyl) -ethylenediamine in 1800 milliliters of water at to 15degrees centigrade with rapid stirring, over a period of one hour. Themixture was stirred for fifteen minutes longer and then allowed toseparate into two layers. 'I'he lower ethylene dichloride layer wasdrawn off and discarded. The remaining aqueous layer was made alkalineby the addition of a solution of 160 grams (3.85 moles) of sodiumhydroxide in 250 milliliters of water and theN-(Z-dimethylaminoethyl)-N-(pmethoxybenzyl) -cyanamide extracted with1600 milliliters of ethylene dichloride. The ethylene dichloride extractwas Washed with water, then dried over anhydrous sodium sulfate. Afterremoval of all the solvent by .distillation under vacuum there remained`660 grams of N-(2-dimethylaminoethyl) N (p methoxybenzyD- cyanamide asa light orange colored liquid. It was found to have a specific gravityof 1.0411 at 25 degrees centigrade, a refractive index of NDZ5 1.5257and a purity of 90.4 percent determined by potentiometric titration topH 6.9.

Eample 43.-Preparation of 1-(2 dimethylaminoethyl) -1-(p-methoazybenzyl) -2-thz'ourea One hundred and fifty-six grams (0.58mole) of 86.8 percent N-(Z-dimethylaminoethyl) -N- (p methoxybenzyl)cyanamide was rapidly stirred at 60 degrees-centigrade and hydrogensulfide passed in during three hours at about atmospheric pressure. TheWeight of the reaction mixture increased by 19 grams or the equivalentof 0.56 mole of hydrogen sulde. It was diluted with 40 milliliters ofcarbon tetrachloride to reduce the viscosity of the mixture and thenpoured into 400 milliliters of cyclohexane. The resulting mixture wasstirred and cooled to 25 degrees centigrade, the iine crystallineproduct filtered off, washed with 200 milliliters of cyclohexane anddried at 50 degrees centigrade. The dry crude 1- (Z-dimethylaminoethyl)-1- (p-methoxybenzyl) -2-thiourea which weighed 161 grams was obtainedas a :une white crystalline powder. This was dissolved in 570milliliters of anhydrous specially denatured alcohol 2B, 81 milliliters(0.575 mole) of alcoholic hydrogen chloride (0.259 gram HC1 permilliliter) added and the hydrochloride allowed to crystallize. Theproduct was filtered off, washed with anhydrous specially denaturedalcohol 2B and dried at 50 degrees centigrade. The dry white crystallineproduct weighed 158 grams and was found to be practically pure 1 (2dimethylaminoethyl) 1 (p methoxybenzyl) 2 thiourea hydrochloride meltingat 158-160 degrees centigrade. On analysis it was found to contain 11.63percent chlorine (theoretical=11.67 percent chlorine).

Various modifications may be made in the method of the present inventionwithout departing from the spirit or scope thereof, and it is to beunderstood that we limit ourselves only as deiined in the appendedclaims.

We claim:

1. A process for the preparation of a substituted thiazole having theformula is a heterocyclic ring selected from the group consisting ofpyrrolidino, piperidino, morpholino,v

thiomorpholino and methylpiperidino and 11. is an integer from 1 to 4,inclusive, which comprises (1) the reaction of cyanogen halide with asecondary amine having the formula in which Y, G and G' have theforegoing significance, to produce the corresponding cyanamide havingthe formula:

29 (2) reacting the resulting cyanamide With hydrogen sulde to producethe corresponding thiourea having the formula and (3) subsequentlyreacting the resultingr thiourea with a carbonyl compound of the groupconsisting of compounds having the formula l Rata-R in which R is aradical of the group consisting of hydrogen, alkyl, aralkyl and arylradicals and X is a halogen of the group consisting of chlorine, bromineand iodine, and acetals of the said carbonyl compounds, and subsequentlyrecovering the resulting substituted thiazole.

2. A process for the preparation of a substituted thiazole having theformula:

is a heterocyclic ring selected from the group consisting ofpyrrolidino, piperidino, morpholino,

thiomorpholino and methylpiperidino and n is an integer from 1 to 4,inclusive, which comprises heating together a substituted thioureahaving the formula 30 with a carbonyl compound of the group consistingof compounds having the formula in which R is a radical of the groupconsisting of hydrogen, alkyl, aralkyl and aryl radicals and X is ahalogen of the group consisting of chlorine, brcmine and iodine, andacetals of the said carbonyl compounds, in an acidic medium, andsubsequently recovering the resulting substituted thiazole.

3. A process as dened in claim 2 in which the temperature of the heatingis maintained between approximately room temperature and approximately vdegrees centigrade.

'4. A process for the preparation of N,Ndi methyl-l\l'(2thenyl) -N (2thiazolyl) ethylenediamine which comprises heating together at atemperature between approximately room temperature and approximately 120degrees centigrade dimethylchloroacetal and l-(2-dimethy1-aminoethyl)-l(2thenyl) 2 thiourea hydrochloride in an acidic medium andsubsequently recovering the resulting N,Ndimethyl-N(2 thenyl) -N'-(2thiazoly1) -ethylenediamine 5. A process for the preparation of N,Ndimethyl-N'-(5-bromo-2-thenyl) -N (2 thiazolyl) -ethylenediamine whichcomprises heating together at a temperature between approximately roomtemperature and approximately 120V degrees centigradedimethylchloroacetal and 1-(2-dimethylaminoethyl)-1-(5-bromo-2 thenyl)2- thiourea in an acidic medium and subsequently recovering theresulting N,Ndirnethyl-N(5 bromo-2-thenyl) -N(2 thiazolyl)ethylenediamine.

CLARENCE W. SONDERN. PHILIP J. BREIVOGEL.

References Cited in the le of this patent UNITED STATES PATENTS NumberName Date 2,106,552 Jenkins Jan. 25, 1938 2,254,136 Buck Aug. 26, 19412,293,027 Ericks Aug. 18, 1942 2,311,281 Roblin Feb. 16, 1943 2,440,703Sondern May 4, 1948 2,502,151 Herclois Mar. 28, 1950 OTHER REFERENCESHuttrer et al.: Enzymologia (Acta Biocatylica), vol. 13, pp. 292, 319,April 26, 1948.

Traumann: Annalen, vol. `249, p. 36.

1. A PROCESS FOR THE PREPARATION OF A SUBSTITUTED THIAZOLE HAVING THEFORMULA